人们常说的“脑子越用越灵”有其内在的神经生物学基础，神经活动能够促进神经元的发育和网络功能构建，神经营养因子可能在其中发挥重要作用。神经元通过轴突输出信息，通过树突接受并整合大量的由突触介导的信息输入，但其形态发生机制尚不完全清楚。10月28日，美国《国家科学院院刊》（PNAS）在线发表了中科院神经科学研究所的最新研究成果，揭示了一种神秘的酶在神经元形态发生中的作用。
异戊二烯基转移酶Geranylgeranyltransferase I (GGT)因能够介导蛋白的翻译后脂化修饰，从而导致多种信号蛋白 (包括 Rho家族的小G蛋白) 的膜转运，成为肿瘤治疗的靶点，但在神经系统的作用完全未知。在罗振革研究员指导下，博士生周秀萍等对该酶在神经发育中的作用进行了深入研究。周秀萍等发现神经活动和脑源性神经营养因子(BDNF)增强GGT的活性，后者引起Rac小G蛋白的膜转运，Rac的膜定位对于后继激活以及树突分支是必需的。进而发现GGT与BDNF的受体TrkB具有直接相互作用并受神经活动的调节，阻断TrkB与GGT的相互作用可以抑制神经元去极化和BDNF引起的树突发育增加。另外，把实验鼠放在新奇的环境中能使海马区GGT的活性快速升高，同时促进Rac的膜定位。该研究揭示了神经活动和BDNF促进树突发育的新机制。
该项工作得到国家科技部、自然科学基金委、上海市科委及科学院的支持，历时3年完成。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS，doi: 10.1073/pnas.0800846105，Xiu-Ping Zhou, Zhen-Ge Luo
TrkB-mediated activation of geranylgeranyltransferase I promotes dendritic morphogenesis
Xiu-Ping Zhou, Kong-Yan Wu, Bin Liang, Xiu-Qing Fu, and Zhen-Ge Luo1
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Abstract
Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho family GTPases. Here we report that activity- and brain-derived neurotrophic factor (BDNF)–dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase that mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by inhibition or down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured hippocampal neurons. Moreover, exploration of a novel environment caused activation of GGT in the mice hippocampus, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization- or BDNF-induced dendrite development. Finally, the GGT effect on dendrite arborization was prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization- or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.
